Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca.sup.2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
EP 0,540,051 and JP 06227971 describe a series of compounds useful as factor Xa inhibitors or to treat influenza based on the formula: ##STR2##
wherein A is an alkylene linker optionally substituted X is a bond, O, S, or carbonyl, n is 0-4, and Y is an optionally substituted carbocycle or heterocycle. The core ring containing Z can be a variety of benzofused heterocycles. However, the present invention does not involve compounds containing these benzofused heterocycles-
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT.sub.1 agonists which are indole substituted five-membered heteroaromatic compounds of the formula: ##STR3##
wherein R.sup.1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not appear to describe heterocycles which are part of the present invention.
Baker et al, in WO 94/02477, discuss 5-HT.sub.1 agonists which are imidazoles, triazoles, or tetrazoles of the formula: ##STR4##
wherein R.sup.1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. But, the presently claimed invention doesn't relate to the heterocyclic cores of Baker et al.
EP 787,727 illustrates benzyl-thiazolidin-2,4-diones of the formula: ##STR5##
which are useful as hypoglycemic agents. However, these type of compounds are outside of the present Xa inhibitors.